Members of the nuclear receptor gene family act as biological rheostats to maintain metabolic homeostasis in response to endocrine and nutritional changes. The liver X (LXR) and thyroid hormone (TR) receptors have been shown to regulate overlapping but distinct metabolic pathways important for overall lipid homeostasis. Dyslipidemia is one out of four key determinants for cardiovascular risk and both LXRs and TRs may provide attractive targets for intervention of cardiovascular disease. In this review we will compare the two receptor systems to highlight similarities and differences in structure and function with implications for development of novel treatments for dyslipidemia and atherosclerosis.